The treatment of pancreatic cancer remains a therapeutic challenge. The majority of patients are unresectable at the time of diagnosis and even in those patients who are resectable, trimodality therapy still has poor outcomes

Due to the location of pancreatic tumors it can be difficult to treat the tumor to high doses and this problem is exacerbated when concurrent chemotherapy is used. This is particularly difficult with a radiosensitizing chemotherapeutic agent such as gemcitabine is used

Local control also remains an issue, which might be improved upon by using higher doses of radiation

Carbon ion therapy may improve outcomes in pancreatic cancer due to its higher RBE and better dose distribution compared with photon based therapy. Carbon ions may have greater effect and higher radiation doses may be able to be used due to carbon’s properties. Additionally, full dose concurrent chemotherapy may become more tolerable with better dose distributions, improving distant control

Results from multiple trials based on prior experiences with carbon ion therapy in locally advanced resectable pancreatic cancer were presented

All patients were felt to have resectable disease that was histologically confirmed

Patients were treated with 8-16 fractions of carbon ion therapy

Overall survival was 30% at 5 years for all patients and was 51% in patients who were resectable

0204

A phase I/II study examining the role of carbon ion therapy in the treatment of patients with unresectable locally advanced pancreatic cancer

Patients were accrued from April 2003-February 2007

Radiation

Doses from 38.4 to 52 CGE were given in 12 fractions over three weeks, four fractions per week

Patients could not have metastatic disease

A total of 46 patients were enrolled

Toxicity

25 patients had grade 2 or greater GI related toxicity

Four patients had grade 2 or greater biliary toxicity

Local control at one year was 81%, but when evaluated by dose, local control was 76% for those patients treated with 43.2 CGE or less, and was 95% for those who were treated with 45.6 CGE or more

Overall survival at one year was 44% for all patients and when assessed by dose, overall survival was 40% in those patients treated with 43.2 CGE or less and was 73% in those patients treated with 45.6 CGE or more

Author's Conclusions

The results of 0204 suggest that hypofractionated carbon ion beam therapy alone was well tolerated with considerable improvement in local control in patients with unresectable pancreatic cancer

However, there did not appear to be a significant benefit in overall survival, though there appeared to be better control with higher doses

These results have spawned further clinical trials which are currently enrolling

Ongoing trials

The first trial involves patients with locally advanced pancreatic cancer treated with a fixed dose of carbon ion therapy to a total dose of 43.2 CGE. The dose of gemcitabine given concurrently is varied and increases from 400 mg/m2 to 700 mg/m2 and finally to 1,000 mg/m2

Initial results from this study suggest that doses of gemcitabine of 1,000 mg/m2 are well tolerated with 43.2 CGE of carbon ion therapy. These data suggest that gemcitabine is better tolerated with carbon ion therapy, as prior studies have suggested that doses of 350-550 mg/m2 are tolerable with other types of radiotherapy. The authors also presented limited survival data, which thus far demonstrated 100% survival in the 1000 mg/m2 group, 84% in the 700 mg/m2 group, and 50% survival in the 200 mg/m2 group.

The authors discuss another trial in which the dose of gemcitabine is fixed at 1,000 mg/m2, while the dose of radiation is to be increased from 45.6 CGE to 48 CGE and finally to 50.4 CGE, as tolerated

Clinical/Scientific Implications

Pancreatic cancer continues to have poor outcomes despite trimodality therapy and a large number of patients with locally advanced disease are unresectable. Due to the location of these tumors critical normal structures, such as the kidneys, liver, small bowel and spinal cord, can make getting high doses to the pancreas difficult.

Carbon ion therapy may improve outcomes in pancreatic cancer due to its higher RBE and better dose distribution compared with photons. These factors may allow higher doses of radiation and/or full dose chemotherapy to be given. The present study suggests that this may be possible as the authors were able to use high doses of gemcitabine with carbon ion therapy. This may improve local control by augmenting radiation’s effects as well as controlling distant disease. However, a major limitation of this presentation is that fields were not described and it is not clear what margins were used and how targets were delineated. Local control was not clearly defined and regional node failures could be higher with smaller fields, though this may be less of a factor if full dose gemcitabine is given concurrently. Further treatment-related information is needed to fully interpret these results as is longer follow up. Furthermore, more detailed toxicity data is needed as there appeared to be a fair number of GI-related toxicity. Nonetheless, these are interesting results suggesting that carbon ion therapy may provide benefit in patients with locally advanced pancreatic cancer.